PROJECT SUMMARY Ebola virus (EBOV) infections remain an emerging threat in Central and West Africa with case fatality rates ranging from 40-90%. The factors that determine susceptibility to lethal EBOV infection are not well understood. Many individuals presenting in EBOV treatment units (ETUs) during the West African EBOV epidemic were acutely infected with or had exposure to P. falciparum, the causative agent of malaria. Emerging data are revealing relationships between severity of EBOV infection outcomes and co-infected with Plasmodium parasites. Some studies conclude that greater mortality is observed in dually-infected populations compared to individuals solely infected with EBOV. Other studies provide evidence that Plasmodium parasite co-infections are protective against EBOV, with those individuals harboring the largest parasite loads exhibiting significant protection against EBOV infection. Using experimental models of EBOV and Plasmodium co-infections, we have identified that acute Plasmodium infection of mice protects against EBOV challenge. By contrast, mice become hyper-susceptible to EBOV as Plasmodium infections resolve and become chronic. We have further linked relative resistance and susceptibility to EBOV to specific pro- and anti-inflammatory cytokines that are produced during acute and chronic Plasmodium infection, respectively. In this project we apply cellular, genetic, and biochemical studies to dissect the impact of malaria on EBOV infection and define the roles of specific pro- and anti-inflammatory inflammatory cytokines in regulating EBOV disease severity. Our goals are addressed by two specific aims that will: 1) determine the timing and mechanisms by which acute malaria protects against EBOV; and 2) identify the specific immuno-regulatory circuits engaged during chronic malaria that render hosts hyper- susceptible to EBOV. Published data and our new preliminary findings establish the relevance and significance of our discoveries and strengthen the scientific premise of our proposed studies. Our studies will establish new paradigms in our understanding of the effect of malaria on EBOV infection and pathogenesis. Our mechanistic studies to elucidate the molecular circuits and pathways by which malaria imparts either resistance or susceptibility to EBOV will identify potential opportunities to therapeutically target or block EBOV infection. Understanding these host-pathogen relationships will be essential for advancing and refining treatment modalities during EBOV outbreaks in malaria endemic areas.